Familial Infertility (Azoospermia and Cryptozoospermia) in Two Brothers—Carriers of t(1;7) Complex Chromosomal Rearrangement (CCR):  Molecular Cytogenetic Analysis

Abstract

Structural aberrations involving more than two breakpoints on two or more chromosomes are known as complex chromosomal rearrangements (CCRs). They can reduce fertility through gametogenesis arrest developed due to disrupted chromosomal pairing in the pachytene stage. We present a familial case of two infertile brothers (with azoospermia and cryptozoospermia) and their mother, carriers of an exceptional type of CCR involving chromosomes 1 and 7 and three breakpoints. The aim was to identify whether meiotic disruption was caused by CCR and/or genomic mutations. Additionally, we performed a literature survey for male CCR carriers with reproductive failures. The characterization of the CCR chromosomes and potential genomic aberrations was performed using: G-banding using trypsin and Giemsa staining (GTG banding), fluorescent in situ hybridization (FISH) (including multicolor FISH (mFISH) and bacterial artificial chromosome (BAC)-FISH), and genome-wide array comparative genomic hybridization (aCGH). The CCR description was established as: der(1)(1qter->1q42.3::1p21->1q42.3::7p14.3->7pter), der(7)(1pter->1p2 1::7p14.3->7qter). aCGH revealed three rare genes variants: ASMT, GARNL3, and SESTD1, which were ruled out due to unlikely biological functions. The aCGH analysis of three breakpoint CCR regions did not reveal copy number variations (CNVs) with biologically plausible genes. Synaptonemal complex evaluation (brother-1; spermatocytes II/oligobiopsy; the silver staining technique) showed incomplete conjugation of the chromosomes. Associations between CCR and the sex chromosomes (by FISH) were not found. A meiotic segregation pattern (brother-2; ejaculated spermatozoa; FISH) revealed 29.21% genetically normal/balanced spermatozoa. The aCGH analysis could not detect smaller intergenic CNVs of few kb or smaller (indels of single exons or few nucleotides). Since chromosomal aberrations frequently do not affect the phenotype of the carrier, in contrast to the negative influence on spermatogenesis, there is an obvious need for genomic sequencing to investigate the point mutations that may be responsible for the differences between the azoospermic and cryptozoospermic phenotypes observed in a family. Progeny from the same parents provide a unique opportunity to discover a novel genomic background of male infertility.

Complex Chromosomal Rearrangement Causes Male Azoospermia: A Case Report and Literature Review

“…According to the classification of CCRs, this case is considered a double CCR. Within more than 250 cases related to CCRs published thus far, 161 cases concerned male CCR carriers (Olszewska et al, 2020). Approximately 75% of CCRs appear de novo or are inherited maternally (70% of all familial cases) (Pellestor et al, 2011;Olszewska et al, 2020).…”

“…Within more than 250 cases related to CCRs published thus far, 161 cases concerned male CCR carriers ( Olszewska et al, 2020 ). Approximately 75% of CCRs appear de novo or are inherited maternally (70% of all familial cases) ( Pellestor et al, 2011 ; Olszewska et al, 2020 ). To date, most men with CCRs have serious fertility problems due to spermatogenesis disorders ( Salahshourifar et al, 2009 ).…”

Familial transmission of chromoanagenesis leads to unpredictable unbalanced rearrangements through meiotic recombination

“…9,25 Indeed, the meiosis I prophase checkpoint is supposed to be less permissive in men than in women, and spermatogenesis is consequently strongly disturbed by complex changes. 11,26,27 During the first division of meiosis, homologous chromosome pairing is a critical step and will be followed by crossing-over. In case of CCR, this step is disturbed and can be completed only through the formation of complex loops between homologs in order to avoid asynaptic segments.…”

“…1,9 It has also been observed that chiasmata numbers are reduced in complex rearrangements, leading to less frequent recombination events. 10,11 Nevertheless, stable and unstable transmissions of chromoanagenesis have been reported. [12][13][14][15][16][17][18][19] We report here six families with one parent presenting chromoanagenesis with unstable transmission of the CCR to the offspring, resulting in congenital disorders.…”

“…As a consequence, CCRs in men are associated with a reduced proportion of normal and balanced gametes and defects in spermatogenesis 1,9 . It has also been observed that chiasmata numbers are reduced in complex rearrangements, leading to less frequent recombination events 10,11 . Nevertheless, stable and unstable transmissions of chromoanagenesis have been reported 12–19 …”